This is an application for the Paul B. Beeson Clinical Scientist Development Award in Aging (K08) for Dr. Annie Hiniker, a Clinical Instructor in Neuropathology at the University of California, San Francisco. The proposal describes a 5-year training program (coursework, conferences, national presentations, and mentored research) for the development of an academic career in the field of neurodegenerative neuropathology, with a particular focus on Parkinson's Disease (PD). This award will provide the core support necessary to establish Dr. Hiniker as an independent researcher in PD and to achieve the following career goals over the five-year term of this award: 1) master techniques in advanced neuroscience, 2) become an expert in PD neuropathology, and 3) develop leadership and mentoring skills necessary to run a top-notch laboratory. To achieve these goals, Dr. Hiniker has developed a plan and assembled a multidisciplinary advisory team of neuroscientists and physician-scientists specializing in cell stress, the unfolded protein response, neurodegenerative neuropathology, and PD genetics and mechanisms. The Applicant: Dr. Hiniker has been studying neurodegenerative disease since her freshman year at Harvard. She graduated from the Medical Scientist Training Program (MSTP) at the University of Michigan Medical School with junior AOA and received the Rackham Distinguished Dissertation award for one of the best dissertations in any field. Her graduate work focused on basic mechanisms of protein folding and misfolding. In June, 2013 Dr. Hiniker graduated from a combined anatomic pathology/neuropathology residency and fellowship at UCSF where she trained in the Physician-Scientist-Pathway. During her residency/fellowship and first year of postdoctoral research, she established novel in vitro, cell culture, and human tissue systems to study the mechanisms of cell death in PD. Through the proposed training program, Dr. Hiniker will expand her scientific skills so as to become an independent investigator studying the neuropathology and basic mechanisms of PD with a career goal of discovering novel therapeutic targets. Mentorship Environment and Formal Instruction: Dr. Hiniker is currently a clinical instructor of neuropathology at UCSF; she is expected to be promoted to a tenure track Assistant Professor within three years; this is not contingent on receiving the award. The proposed training program draws on the combined resources of the Oakes and Nussbaum Laboratories, the UCSF Institutes of Neurodegenerative Disease and Quantitative Biosciences, and the UCSF Division of Neuropathology. Scott Oakes, MD, and Bob Nussbaum, MD, will mentor the candidate's scientific development. Dr. Oakes is Associate Professor of Pathology with Tenure and an expert in protein folding stress responses in the cell; he has exceptional mentorship experience as Head of Advising of the UCSF Biomedical Sciences Graduate Program and Lead PI on a T32 postdoctoral training grant. Dr. Nussbaum is Holly Smith Distinguished Professor in Science and Medicine, Chief of the Division of Medical Genetics, and the neuroscientist who discovered the a-synuclein gene. He has made major advances in the study of PD and his record of mentoring residents, postdocs, and students is outstanding. To enhance Dr. Hiniker's training, an advisory committee of highly-regarded senior scientists including Drs Oakes and Nussbaum will provide scientific and career advice. This advisory committee also includes a neuroscientist specializing in protein misfolding in neurodegenerative disease (Stanley Prusiner, MD, Director of the UCSF Institute of Neurodegenerative Disease); a neuropathologist (Marta Margeta, MD, PhD, Assistant Professor of Neuropathology); and a proteomics expert (Nevan Krogan, PhD, Director of the California Institute of Quantitative Biosciences at UCSF). Dr. Hiniker's knowledge will be supplemented by advanced classes and seminars at UCSF, Cold Spring Harbor, and by structured one-on-one instruction with Dr. Thomas Montine at the University of Washington. Research: PD is the second most common neurodegenerative disorder and a significant cause of morbidity, mortality, and financial cost. Dr. Hiniker's long-term goal is to identify the molecular mechanisms of cell death in PD in order to find novel pathways that can be translated into rational therapeutics for PD. The objective of this project is to dissect the role of the Lrrk2 kinase in PD cell death pathways using complementary targeted approaches and large scale screens in both cell culture and human brain tissue via the following specific aims: 1) Determine the impact of Lrrk2 kinase activity on the signaling of Ire1a--master regulator of the unfolded protein response; 2) Define interdependency between the Lrrk2 kinase and GTPase domains; and 3) Delineate the Lrrk2 kinase-dependent and -independent cellular interactome. This research uses cell biology and biochemistry as well as human tissue studies to answer important questions about PD. This project follows the mission of the NIH and more specifically of the Paul B. Beeson RFA to further research on neural processes in the aging brain.